Regenerative Calcium Currents in Renal Primary Cilia

Polycystic kidney disease (PKD) is a leading cause of end-stage renal disease. PKD arises from mutations in proteins, one a Ca -conducting channel, expressed in the primary cilia of renal epithelial cells. A common hypothesis is that Ca entering through ciliary ion channels may reduce cystogenesis. The cilia have at least two Ca -conducting channels: polycystin-2 (PC2) and TRPV4 (transient receptor potential (TRP) cation channel, subfamily V, member 4), but how substantially they can increase intraciliary Ca is unknown. By recording channel activities in isolated cilia, conditions are identified under which the channels can increase free Ca within the cilium by at least 500-fold through regenerative (positive-feedback) signaling. Ca that has entered through a channel can activate the channel internally, which increases the Ca influx, and so on. Regenerative signaling is favored when the concentration of the Ca buffer is reduced or when a slower buffer is used. Under such conditions, the Ca that enters the cilium through a single PC2 channel is sufficient to almost fully activate that same channel. Regenerative signaling is not detectable with reduced external Ca . Reduced buffering also allows regenerative signaling through TRPV4 channels, but not through TRPM4 (TRP subfamily M, member 4) channels, which are activated by Ca but do not conduct it. On a larger scale, Ca that enters through TRPV4 channels can cause secondary activation of PC2 channels. I discuss the likelihood of regenerative ciliary Ca signaling , a possible mechanism for its activation, and how it might relate to cystogenesis.